Breast cancer results from the accumulation of alterations to the genome, such as mutations, acquired or inherited, chromosomal re-arrangements, and deviations from the diploid chromosome number. Together, these genetic changes can allow cells to bypass cellular growth control mechanisms. One such mechanism is the spindle checkpoint. The proteins of the spindle checkpoint prevent progression of the cell into anaphase until all chromosomes are properly attached to microtubules. The spindle checkpoint is implicated in both the origins and treatment of breast cancer. Studies have failed to show any universal defect in the spindle checkpoint genes in breast tumors. Under-expression or defects in the spindle checkpoint genes can contribute to chromosome instability in tumors.
The spindle checkpoint is also important for the treatment of breast cancer. The anti-tumor drug, taxol, halts cell growth by altering microtubule dynamics in a way that activates the spindle checkpoint, resulting in cell cycle arrest, and ultimately, apoptotic cell death. Weakening of the spindle checkpoint may be one avenue to the resistance of tumor cells to taxol.
Breast cancer is thought to result from the accumulation of alterations to the genome, such as mutations, acquired or inherited, chromosomal re-arrangements, and deviations from the normal chromosome number. Such chromosomal changes defined as “aneuploid” compare to normal “euploid” chromosome arrangements and number. Together, these genetic changes allow the cancer cells to avoid the mechanisms that control cell growth.
One of the mechanisms used to control growth and retain the proper chromosome number in normal cells is called the spindle checkpoint. The spindle checkpoint is a surveillance mechanism that stops cells from undergoing what could be an errant division that would result in an inappropriate number of chromosomes in the daughter cells. The spindle checkpoint machinery is able to do this by monitoring the attachment of the chromosomes to the cellular cables (called microtubules) that pull the chromosomes into the two daughter cells. If a chromosome fails to attach to the cables, the spindle checkpoint machine produces a signal that blocks the cell division process. If the cell fails to fix the problem, the cell is usually programmed to die by apoptosis. While this might seem drastic, it is advantageous for the body to kill occasional “problem” cells rather than risk creating a cell with the wrong number of chromosomes, because having the wrong number of chromosomes can lead to a cell becoming a cancer cell.
In recent years, one of the most effective anti-breast cancer drugs has been taxol. Taxol causes a structural problem with the cables that pull chromosomes into daughter cells. As a consequence, the spindle checkpoint mechanism senses the problem with the attachment of the taxol-treated cables to the chromosomes, and prevents cell division. This results in cell death. Tumors that do not respond to taxol may have defects in the spindle checkpoint system, which prevent the defective spindle checkpoint from sensing the problems with the taxol-treated cables, so that the cells can avoid the arrest and death.
Novel anti-tumor agents are needed to treat tumors that do not respond to taxol or that do not respond to other anti-cancer agents, and to treat tumors that have acquired resistance to anti-cancer agents.